PT  - JOURNAL ARTICLE
AU  - Sonia R. Miranda
AU  - Jin Kyung Lee
AU  - Kim L. R. Brouwer
AU  - Zhiming Wen
AU  - Philip C. Smith
AU  - Roy L. Hawke
TI  - Hepatic Metabolism and Biliary Excretion of Silymarin Flavonolignans in Isolated Perfused Rat Livers: Role of Multidrug Resistance-Associated Protein 2 (Abcc2)
AID  - 10.1124/dmd.108.021790
DP  - 2008 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 2219--2226
VI  - 36
IP  - 11
4099  - http://dmd.aspetjournals.org/content/36/11/2219.short
4100  - http://dmd.aspetjournals.org/content/36/11/2219.full
SO  - Drug Metab Dispos2008 Nov 01; 36
AB  - Silymarin, an extract from seeds of Silybum marianum, is used by 8 to 33% of patients to self-treat chronic viral hepatitis C in the United States. Studies in humans and rodents suggest that biliary excretion of glucuronide and sulfate conjugates is the major route for silymarin's elimination. To determine the role of multidrug resistance-associated protein 2 (Mrp2) (Abcc2) in the biliary excretion of silymarin, the hepatobiliary disposition of the six major silymarin flavonolignans was studied using isolated perfused livers (IPRLs) from wild-type (WT) and Mrp2-deficient (TR-) Wistar rats. For all the flavonolignans, approximately 96% of the dose was cleared from perfusate within 30 min in both WT and TR- livers, and <5% of parent was recovered in bile or perfusate by the end of the perfusion. In WT livers, the percentage of dose excreted as conjugates into bile varied for each flavonolignan (silychristin, 51.6 ± 9.3%; silydianin, 101.5 ± 28.3%; silybin A, 21.0 ± 8.3%; silybin B, 31.7 ± 13.2%; isosilybin A, 50.5 ± 23.6%; isosilybin B, 42.8 ± 19.3%). Among the flavonolignans, only silydianin was primarily glucuronidated and almost completely recovered in bile. In TR- livers, biliary excretion of flavonolignan conjugates was reduced 80 to 92%, with 30 to 83% of each flavonolignan conjugate recovered in perfusate compared with only 5 to 30% at 90 min. Biliary excretion of glucuronide and sulfate conjugates of all the flavonolignans were reduced by 94 to 98% and 73 to 84%, respectively, in TR- IPRLs. These data indicate a primary role for Mrp2 in the biliary elimination of silymarin flavonolignan conjugates. The American Society for Pharmacology and Experimental Therapeutics